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Vol. 58, Issue 5, 946-953, November 2000

Evidence That Galpha q-Coupled Receptor-Induced Interleukin-6 mRNA in Vascular Smooth Muscle Cells Involves the Nuclear Factor of Activated T Cells

Karen L. Abbott, James R. Loss, II, Aaron M. Robida, and T. J. Murphy

Department of Pharmacology and Graduate Program in Molecular and Systems Pharmacology, Emory University School of Medicine, Atlanta, Georgia

The immunosuppressant cyclosporin A inhibits transcription mediated by the nuclear factor of activated T-cells (NFAT), a key regulator of cytokine gene expression in lymphocytes that integrates phospholipase C signaling. NFAT is also expressed in vascular smooth muscle cells, but the genes it regulates there are unknown. Here we show that Galpha q-coupled P2Y nucleotide receptor signaling in rat vascular smooth muscle cells increases NFAT-mediated luciferase reporter expression. It also induces interleukin (IL)-6 gene expression but not other cytokine mRNAs including IL-1, IL-2, IL-3, IL-4, IL-10, gamma -interferon, tumor necrosis factor-alpha , or tumor necrosis factor-beta . IL-6 mRNA induction by UTP is more rapid and transient then that caused by IL-1beta stimulation and is partially blocked by cyclosporin A or by expression of a trans-dominant NFAT inhibitor. Expression of recombinant NFATc1 markedly augments IL-6 mRNA induction by these and other agonists, which is partially attributable to NFAT-regulated paracrine mediators. However, trans-dominant NFkappa B inhibitors strongly interfere with IL-6 mRNA induction both by IL-1beta and by UTP, which synergistically evoke IL-6 mRNA expression. These findings suggest that NFAT is among the cofactors involved in NFkappa B-dependent IL-6 gene induction by Ca2+-mobilizing receptors in vascular smooth muscle cells.


Copyright © 2000 by The American Society for Pharmacology and Experimental Therapeutics



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